The Bulgarian side went into the tie with confidence after beating Lazio to reach the last 16 for the first time, but their Spanish visitors got off to a flyer and overcame having to play more than half of the game with 10 men.
Right-back Antonio Barragan fired Valencia into the lead after only five minutes as he blasted a low half-volley past the helpless Vladislav Stoyanov for his first goal since November 2010.
Ludogorets were given a great chance to restore parity with a penalty as Seydou Keita received a straight red card, but Diego Alves palmed Roman Bezjak's 26th-minute effort away and Fede Cartabia grabbed Valencia's second soon after.
Philippe Senderos headed in a third with 31 minutes to go, before Juninho Quixada was dismissed to compound the misery for a Ludogorets side suffering their first Europa League defeat of the season.
Valencia coach Juan Antonio Pizzi spent the build-up to the game talking up his side's chances of winning the competition and they got off to a perfect start in Sofia, over 300 kilometres from Ludogorets' usual Razgrad home.
The hosts partially cleared Eduardo Vargas' free-kick from the left, but Barragan latched on to the loose ball on the edge of the area and drilled a low half-volley into the bottom-left corner.
Ludogorets were handed a lifeline 24 minutes in as Keita was controversially sent off for clumsily denying Bezjak a goal-scoring opportunity in the area, but Alves - a goalkeeper boasting an excellent record when it comes to saving penalties - kept out the subsequent spot-kick.
Valencia narrowly escaped again just after the half-hour mark as Virgil Misidjan hit the post after cutting in from the left, and Pizzi's men capitalised by doubling their lead almost immediately despite Ludogorets' numerical advantage.
Alcacer saw his chipped pass deflect into the area and Cartabia met it with a first-time volley, directing the ball into the bottom-right corner.
Ludogorets finished the half well as Marcelinho and Misidjan both went close from outside the area.
Stoycho Stoev's men also began the second period in determined fashion, putting Valencia under intense pressure, but the La Liga side defended well and restricted Ludogorets to long-range efforts before putting the tie beyond all doubt.
Vargas headed a corner from Cartabia back across the face of goal and Senderos was left unmarked to nod the ball into the bottom-right corner.
Ludogorets' day got even worse with 10 minutes to go as Quixada picked up a red card for seemingly kicking out at the theatrical Joao Pereira, allowing Valencia to see out the closing stages with consummate ease.
